Granulomas have traditionally been classified into two categories, non-immunologic (foreign body) and immunologic (hypersensitivity), although there may be overlap.
Human granulomatrous inflammation occurs against known antigens such as mycobacteria, fungi, parasites, and foreign particles such as talc and beryllium. These antigens are not capable of being phagocytized and cleared by polymorphonuclear cells. However, in human granulomatous diseases such as sarcoidosis, Wegener's granulomatosis, primary biliary cirrhosis and Crohn's disease, no inciting antigen has been identified and the idiopathic granulomatous inflammation can be physiologically detrimental. There have been no satisfactory experimental models for the study of human granulomatous inflammation and hence many questions remain unanswered concerning the immunology, regulation of granulomas and appropriate clinical treatment
Investigations of the mechanisms regulating human granulomatous inflammation have been limited by the lack of suitable animal and in vitro models. The earliest bead model of granulomatous inflammation was the mouse pouch assay where polyacrylamide beads were injected into a subcutaneous air filled skin pouch. The resulting cellular infiltrates in the pouch were predominantly mononuclear cells forming granulomata. Subsequently, immunologic reactions were successfully modeled in vitro using antigen coated polyacrylamide beads and peripheral blood mononuclear cells (PBMC). The PBMC, in the absence of autologous sera, react to polyacrylamide beads coated with the proper antigen, reflecting the immune status of the host.
Non-immunologic, foreign body granulomas have been studied in guinea pigs (Turk, J.L. et al., "The mononuclear phagocyte system in granulomas", Brit. J. Derm. 1985; 113:49-54), mice (Takizawa et al., "Granulomatous pneumonitis induced by Bacille Calmette-Guerin in the mouse and its treatment with cyclosporin", 1986; 134:296-299) and athymic rats (Chang et al., "Histology of granulomatous inflammation in nude rats lungs induced by complete Freund's Adjuvant (CFA)" In: Grassi et al. Sarcoidosis and Other Granulomatous Disorders, Amsterdam: Excerpta Medica; 1988, pp. 717-718). Non-immunologic granulomas can also be produced by foreign body injection such as Sepharose-4B into mice (Carrick and Boros, "The artificial granuloma 1: in vitro lumphokine production by pulmonary artificial hypersensitivity granulomas", Clin Immun and Immunopath, 1980: 17:415-426), talc into rabbits (Horowitz et al., "Angiotensin converting enzyme concentrations in rabbit with talc-induced pulmonary, granulomatosis", Am Rev Resp Dis, 1981; 124:306-309) and Sephadex beads into mice (Remick et al., Flow-cytometric evaluation of lymphocyte subpopulations in synchroncusly developing schistosoma mansoni egg and sephadex bed pulmonary granulomas" , Am J Path, 1988; 131:298-307). All of these animal models of non-immunologic granulomas provide little information concerning the mechanisms of human immunologic granulomatous inflammation.
Immunologic granulomas in animals have been recently produced by injections of beryllium in mice (Newman, "Antigen-specific T-cells in a mouse model of beryllium disease. In: Grassi C , Rizzato G. Pozzi E., eds.: Sarcoidosis and Other Granulomatous Disorders, Amsterdam: Excerpta Medica; 1988, pp. 715-716) and latex beads covered with interleukin-1 (Kasahara et al., "Direct evidence for granuloma-inducing activity of interleukin-1: induction of experimental pulmonary granuloma formation in mice by interleukin-1-coupled beads", Am J Path, 1988, 130:629-637) demonstrating that selected foreign materials may account for non-immunologic versus immunologic granuloma formation.
Immunologic granuloma formation and regulation has been extensively studied in schistosomiasis using animal and human PBMC exposed to schistosoma whole eggs to form in vitro granulomas (IVG's) (Boros, D.L., "Immunoregulation of granuloma formation in murine schistosomiasis mansoni", Ann NY Acad Sci, 1986; 465:313-323; de Brito et al., "Host granulomatous response in Schistosoma mansoni-antibody and cell-mediated damage of parasite eggs in vitro", J Clin Invest, 1984; 74:1715-1723; Doughty et al., "Delayed type hypersensitivity granuloma formation around Schistosoma mansoni eggs in vitro", Am J Trop Med Hyg 1984; 33:1173-1177; Ohta et al., "Schistosoma japonicum egg antigen-specific T-cell lines in man-induction of helper and suppressor T-cell lines and clones in vitro in a patient with chronic Schistosoma japonica", J Clin Invest, 1988; 81:775-781). These in vitro granuloma (IVG) models disclosed a cell-mediated response and were refined by substituting the whole schistosoma eggs with latex beads coated only with purified schistosoma soluble egg antigen (SEA). Culturing these beads with PBMC, T-cell clones or spleen cells in the absence of autologous serum proved to be the first practical in vitro models suited to study mechanisms regulating granuloma formation (Bentley et al., In vitro delayed hypersensitivity granuloma formation-development of an antigen-coated bead model", J ImmunoI, 1985; 134:4163-4169). The method of quantitating the immune contribution of cells in schistosomiasis-induced IVG's was according to the IVG size After 7 days in vitro, either PBMC and T-cells from patients or animals with active schistosomiasis showed enhanced cell adherence to the bead with larger IVG formation while cells from patients or animals not infected with schistosomiasis resulted in smaller IVG's. This model of chronic granulomatous inflammation was limited by dependency on the measurement of in vitro granuloma size to assess disease activity, e.g., differences between the most active and least active in vitro granulomas were often the adherence of only 1-2 cells per bead with over two million cells present. This lack of sensitivity and specificity of the in vitro granulomas in schistosomiasis limited this model's popularity.
Human granulomatous infections, such as sarcoidosis and Wegener's granulomatosis, have no known cause or cure. Granuloma formation in sarcoidosis is generally thought to result from T-cell and macrophage activation in response to a putative antigen, and has not been regarded as governed by circulating factors. Despite years of research, no such antigen has been discovered. No blood test for the presence of human granulomatous inflammation diseases currently exists. Present treatment has been confined to the use of dangerous immunosuppression drugs such as prednisone and cyclophosphamide.